title: Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer.
abstract: BACKGROUND
  Preclinical studies show that opioids stimulate angiogenesis and tumor progression through the mu opioid receptor (MOR). Although MOR is overexpressed in several human malignancies, the effect of chronic opioid requirement on cancer progression or survival has not been examined in humans.
  
  
  METHODS
  We performed a retrospective analysis on 113 patients identified in the Minneapolis VA Tumor Registry (test cohort) and 480 patients from the national VA Central Cancer Registry (validation cohort) who had been diagnosed with stage IV prostate cancer between 1995 and 2010 to examine whether MOR expression or opioid requirement is associated with disease progression and survival. All opioids were converted to oral morphine equivalents for comparison. Laser scanning confocal microscopy was used to analyze MOR immunoreactivity in prostate cancer biopsies. The effects of variables on outcomes were analyzed in univariable and multivariable models.
  
  
  RESULTS
  In patients with metastatic prostate cancer, MOR expression and opioid requirement were independently associated with inferior progression-free survival (hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.33-2.07, P<.001 and HR 1.08, 95% CI 1.03-1.13, P<.001, respectively) and overall survival (HR 1.55, 95% CI 1.20-1.99, P<.001 and HR 1.05, 95% CI 1.00-1.10, P = .031, respectively). The validation cohort confirmed that increasing opioid requirement was associated with worse overall survival (HR 1.005, 95% CI 1.002-1.008, P = .001).
  
  
  CONCLUSIONS
  Higher MOR expression and greater opioid requirement are associated with shorter progression-free survival and overall survival in patients with metastatic prostate cancer. Nevertheless, clinical practice should not be changed until prospective randomized trials show that opioid use is associated with inferior clinical outcomes, and that abrogation of the peripheral activities of opioids ameliorates this effect.
authors.affiliation: Division of Hematology/Oncology/Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota; Hematology/Oncology Section, Department of Medicine, Minneapolis VA Health Care System, Minneapolis, Minnesota.
authors.forename: Dylan
authors.initials: D
authors.lastname: Zylla
authors.forename: Brett L
authors.initials: BL
authors.lastname: Gourley
authors.forename: Derek
authors.initials: D
authors.lastname: Vang
authors.forename: Scott
authors.initials: S
authors.lastname: Jackson
authors.forename: Sonja
authors.initials: S
authors.lastname: Boatman
authors.forename: Bruce
authors.initials: B
authors.lastname: Lindgren
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kuskowski
authors.forename: Chap
authors.initials: C
authors.lastname: Le
authors.forename: Kalpna
authors.initials: K
authors.lastname: Gupta
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000401:mortality* / Q000473:pathology; D017450:Receptors, Opioid, mu / Q000032:analysis*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu
keywords: humans; morphine; mortality; mu opioid receptors; opioid analgesics; opioid receptors; opioids; pain; prostatic neoplasms; retrospective studies